Arbidol has been reported to have inhibitory effects on a diverse array of viruses such as influenza, Zika virus, respiratory syncytial virus, adenovirus, Coxsackie B5, parainfluenza, Ebola and hepatitis B and C viruses [3,4,5,6,7]. Mechanismly, it inhibited the fusion of influenza virus with endosomal membrane through binding to a hydrophobic cavity in the hemagglutinin on virus surface and stabilizing the pre-fusion conformation of hemagglutinin [5]. Owing to the broad-spectrum efficacy, Arbidol has been licensed for prophylaxis and treatment of acute respiratory infections, including influenza in China and Russia [5]. As for COVID-19, Chen et al. [8] found no difference between Lopinavir/Ritonavir and Arbidol in relieving symptoms or accelerating virus clearance. However, the subsequent multicenter, prospective research carried out by Wei et al. [9] demonstrated that the triple combination antiviral therapy of Arbidol, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy without Arbidol. They also found that 10–30 μmol/L Arbidol effectively inhibited the coronavirus 60-fold compared with the untreated control group, as well as significantly alleviated the injury of SARS-CoV-2 to cells by chemosensitivity testing in vitro (Data were not published). Herein, we discovered the efficacy of Arbidol on viral shedding, thus accelerating disease relief in the nonemergency COVID-19 patients. We noticed that males displayed higher fever and more COVID-19 symptoms, which might due to the up-regulated SARS-Cov-2 receptor, angiotensin‐converting enzyme 2 (ACE2) by smoking and testosterone level, as well as excessive immune-inflammatory response [10, 11]. Furthermore, males exhibited better drug response, suggesting certain microenvironment (such as pH, ion, hormone and cytokines) might strengthen the efficacy of Arbidol. More studies in vivo and in vitro could be performed to identify the exact mechanisms.
Several results deserved explanations. Arbidol shortened fever duration compared with the patients without Arbidol and with other antiviral drugs respectively (Figs. 1, 2). The effect seemed more prominent when given early in the disease and in male patients. As shown in Fig. 1e, combination of Arbidol and other antiviral drugs did not show better efficacy compared to Arbidol only. We speculated the reduction in the first 5 days of fever period was mainly due to Arbidol and application of several antiviral drugs simultaneously might have aggravated adverse reaction or induced multiple adverse reactions. Additionally, all patients in Arbidol + other antiviral drugs group achieved negative nucleic acid in their respiratory specimens, but not in Arbidol only group (Table 3), though the difference was insignificant. We suggested that the number of subjects was not enough, therefore leading to certain inconsistency in the result.
Despite efforts to exclude bias by critical analysis, there were still several limitations in our research. First of all, this was a retrospective study and has not undergone rigorous clinical trial design. Therefore, it could not provide direct evidence for the effectiveness of Arbidol among COVID-19 patients. However, these results provided implications for further experimental or clinical researches on Arbidol usage and even guided the development of novel therapeutics against SARS-CoV-2. Secondly, during the early onset (from January to February, 2020) of the disease in this cohort, the treatment therapies might not accord with the latest guideline. These relatively mild patients were mainly administrated with Arbidol and/or Oseltamivir as antiviral treatments because of the rescuing urgency. In that case, we excluded the bias of antibiotic and traditional Chinses medicine which were widely used in our cohort (Tables 1, 2) and found the significant results of Arbidol. It should be noted that the efficacy might attribute to the combined effects, such as Arbidol combined with Chinses medicine. This deserved further studies in a larger cohort. Thirdly, the patients were hospitalized in shelter hospital (originated from gymnasiums, convention center and so on), where laboratory tests and chest CT could not be carried out promptly as a consequence of equipment and faculty deficiency. Therefore, our efficacy evaluation system was not perfect. Viral nuclei acid detection could not be performed everyday nor within 7 days since the first diagnosis; thus, we selected negative-conversion within 14 days as the indication of better drug response. This study aimed to bring more researches enlightenment in understanding the emerging infectious disease. Despite this, we also suggested the double-blinded randomized clinical trials on Arbidol application in COVID-19 patients, especially in mild and common type.